Annual Reports in Medicinal Chemistry (eBook)

Cover 1
Contents 6
Contributors 16
Preface 18
Part I: Central Nervous System Diseases – ROBICHAUD 20
Chapter 1. Potential CNS Applications for Phosphodiesterase Enzyme Inhibitors 22
1. Introduction 22
2. PDE2 Inhibitors 23
3. PDE4 Inhibitors 25
4. PDE9 Inhibitors 26
5. PDE10 Inhibitors 27
6. PDE11 Inhibitors 29
7. Summary 29
References 30
Chapter 2. Recent Developments in Monoamine Reuptake Inhibitors 32
1. Introduction 32
2. Single Action Reuptake Inhibitors 33
3. Dual Reuptake Inhibitors 37
4. Triple Reuptake Inhibitors (TRIs) 40
5. Conclusion 42
References 42
Chapter 3. Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease 46
1. Introduction 46
2. Inhibitors of BACE 47
3. Inhibitors of .-Secretase 53
4. Modulators of .-Secretase 58
5. Summary 61
References 61
Chapter 4. Recent Advances in Drug Discovery of Histamine H3 Antagonists 68
1. Introduction 68
2. Clinical Applications of H3 Receptor Antagonists 70
3. Pharmacophores and Modeling 72
4. Design Strategies and Structure–Activity Advances 72
5. H3 Antagonists with a Dual Mechanism 77
6. Future Perspectives 78
References 78
Chapter 5. Recent Advances in the Treatment of Insomnia 82
1. Introduction 82
2. GABAA Receptor Modulators 84
3. Melatonin Receptor Agonists 87
4. Orexin Receptor Antagonists 90
5. Histaminergic and Serotoninergic Modulators 94
6. Concluding Remarks 96
References 97
Chapter 6. Advances in Transient Receptor Potential Modulators 100
1. Introduction 100
2. Small Molecule TRP Modulators 101
3. Conclusion 108
References 108
Part II: Cardiovascular and Metabolic Diseases – STAMFORD 112
Chapter 7. Case History: JANUVIA’ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes 114
1. Introduction 114
2. Pathogenesis of Type 2 Diabetes 115
3. Rationale for the Use of DPP-4 Inhibitors to Treat Type 2 Diabetes 116
4. MRL’s DPP-4 Inhibitor Program: Threo- and Allo-Isoleucyl Thiazolidides 117
5. Medicinal Chemistry Efforts Leading to Sitagliptin 119
6. Properties of Analog 27 and Sitagliptin 124
7. Clinical Studies of Sitagliptin 125
8. Conclusion 126
References 126
Chapter 8. Cathepsin K Inhibitors 130
1. Introduction 130
2. New Biology 131
3. Recent Advances in Inhibitor Design 135
4. Clinical Data 142
5. Conclusions 143
Acknowledgement 143
References 143
Chapter 9. New Nonpeptide-Binding GPCRs as Targets for Diabetes and the Metabolic Syndrome 148
1. Introduction 148
2. GPR119 149
3. GPR40 Family 153
4. GPR120 157
5. GPR55 and GPR35 157
6. GPR109A and GPR109B 158
7. Conclusions 160
References 160
Chapter 10. Novel Selective Estrogen Receptor Modulators (SERMs) 166
1. Introduction 166
2. SERMs for Hot Flushes 167
3. Ovarian Selective SERMs 168
4. ERa Selective Serms 170
5. Other Novel Serm Scaffolds 172
6. Steroid-Derived Scaffolds 174
7. Nonclassical Estrogen Signaling 175
8. Conclusion 176
References 177
Chapter 11. Lipid-Metabolizing Enzymes as Targets for Dyslipidemia and Insulin Resistance 180
1. Introduction 180
2. Lipid Absorption and Mobilization 181
3. Triglyceride Synthesis 184
4. Fatty Acid Synthesis and Metabolism 186
5. Conclusion 190
References 191
Chapter 12. Recent Trends in HDL Modulating Therapies 196
1. Introduction 196
2. HDL and Atherosclerosis 197
3. Scope and Limitations of Marketed Therapies 197
4. Emerging Clinical Compounds 202
5. Pre-Clinical Developments 205
6. Conclusion 206
References 207
Part III: Inflammation/Pulmonary/GI – BARRISH 212
Chapter 13. Case History on Tegaserod (Zelnormreg®/Zelmacreg®) 214
1. Introduction 214
2. Discovery of the 5-HT4 Receptor in the GI Tract 215
3. Test Systems Addressing 5-HT4 Receptor Agonist Activity 216
4. From Serotonin to Tegaserod 218
5. Profiling Studies 222
6. Clinical Phase II/III Studies 225
7. Conclusion 226
References 227
Chapter 14. Advances in the Discovery of CC Chemokine Receptor 2 Antagonists 230
1. Introduction 230
2. Recent Biology 231
3. Recent Medicinal Chemistry 234
4. Conclusion 242
References 242
Chapter 15. Semicarbazide Sensitive Amine Oxidase and Vascular Adhesion Protein-1: One Protein Being Validated as a Therapeutic Target for Inflammatory Diseases 248
1. Introduction 249
2. Molecular Biology of the Copper-Containing Amine Oxidase Family 251
3. Co-factor and Mechanism of the Amine Oxidase Activity 252
4. Structural Biology 252
5. Therapeutic Opportunities 253
6. Drug Discovery 254
7. SSAO/VAP-1 Inhibitors 254
8. Conclusion 259
9. Abbreviations 259
References 260
Chapter 16. Sphingosine 1-Phosphate Type 1 Receptor Modulators: Recent Advances and Therapeutic Potential 264
1. Introduction 264
2. S1P1 Agonists 268
3. S1P1 Antagonists 277
4. Conclusions 278
References 279
Chapter 17. MAP Kinase Inhibitors in Inflammation and Autoimmune Disorders 284
1. Introduction 284
2. Inhibitors of ERK Pathway 287
3. Inhibitors of JNK Pathway 289
4. Inhibitors of p38 Pathway 293
5. Conclusion 294
References 294
Part IV: Cancer and Infectious Diseases – MYLES 298
Chapter 18. Recent Progress on Novel HCV Inhibitors 300
1. Introduction 300
2. Novel Compounds in the Discovery/Preclinical Stage 301
3. Conclusion 313
References 313
Chapter 19. Small Molecule CCR5 and CXCR4-Based Viral Entry Inhibitors for Anti-HIV Therapy Currently in Development 320
1. Introduction 320
2. CCR5 Inhibitors 321
3. CXCR4 Inhibitors 328
4. Conclusions 334
Note 335
References 335
Chapter 20. Small-Molecule Inhibitors of Glutathione S-Transferase P1-1 as Anticancer Therapeutic Agents 340
1. Introduction 340
2. Types of Inhibitors 341
3. Conclusions 351
References 351
Chapter 21. Recent Advances in the Medicinal Chemistry of Histone Deacetylase Inhibitors 356
1. Introduction 356
2. Zinc-Dependent HDAC Inhibitors 357
3. NAD-Dependent HDAC Modulators 363
4. Conclusion 365
References 365
Chapter 22. New Developments in Antibacterial Drug R& D
1. Introduction 368
2. Updates of Established Classes of Antibiotics 372
3. Future Antibacterial Pipeline: Inhibitors of New Targets 377
4. Future Outlook 379
References 380
Chapter 23. Small Molecule Inhibitors of AKT/PKB Kinase as a Strategy for Treating Cancer 384
1. Introduction 384
2. PI3K/AKT Kinase Pathway Inhibitors in Pre-Clinical Development 385
3. PI3K/AKT Kinase Pathway Inhibitors in Clinical Trials 390
4. Conclusions 392
References 392
Part V: Topics in Biology – LOWE 396
Chapter 24. Spleen Tyrosine Kinase (Syk) Biology, Inhibitors and Therapeutic Applications 398
1. Introduction 398
2. Syk Kinase 399
3. Structural Biology of Syk Kinase 399
4. Syk Kinase as a Therapeutic Target for Disease 401
5. Status of Small Molecule Inhibitors of Syk Kinase 405
6. Conclusion 408
References 408
Chapter 25. Systems Biology and Kinase Signaling 412
1. Complexity and Scope in Systems Kinase Biology 412
2. Positive and Negative Feedback Loops 413
3. An Example of the Practical Application of Systems Biology: ErbB Signaling 415
4. Conclusion 418
5. Acronyms Used 418
References 419
Chapter 26. The Molecular Libraries Screening Center Network (MLSCN): Identifying Chemical Probes of Biological Systems 420
1. Introduction 421
2. Role of Chemistry in the MLSCN 427
3. Novel Probes from the MLSCN 428
4. Future Outlook and Conclusions 433
References 434
Chapter 27. The Application of Transcriptional Profiling in Model Connectivity and Lead Assessment in Drug Discovery 436
1. Introduction 436
2. Transcriptional Profiling Technology: State of the Art, and Foreseeable Future 437
3. Interconnecting Disease, Target Validation Models, and Pharmacological Response 438
4. Comparing Selectivity of Pharmacological Response in Lead Assessment 441
5. Conclusions 444
References 445
Part VI: Topics in Drug Design and Discovery – DESAI 448
Chapter 28. Fragment-Based Lead Discovery 450
1. Introduction 450
2. Examples of Fragment Hit Identification 451
3. Examples of Fragments Progressed into Nanomolar Leads 454
4. Commentary and Discussion of Key Concepts 462
5. Outlook 464
References 465
Chapter 29. Computational Models for ADME 468
1. Introduction 468
2. Basic Computed Descriptors for Drug-Likeness 470
3. Solubility 471
4. Intestinal Absorption 474
5. Blood-Brain-Barrier Penetration 476
6. Metabolism 482
7. Conclusion 483
References 484
Chapter 30. Prediction of Human Volume of Distribution Using in vivo, in vitro, and in silico Approaches 488
1. Introduction 488
2. Definitions of Volume of Distribution 489
3. Predicting Human Volume of Distribution from Chemical, in vitro, and in vivo Data 493
4. Conclusions 504
References 507
Chapter 31. Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications 508
1. Introduction 508
2. Refinements in Understanding of the Free Drug Principle 509
3. Applications from the Medicinal Chemistry Literature 513
4. Computational Studies 516
5. Exceptions to the Free Drug Principle 517
6. Advances in Methodology for Measuring Plasma Protein Binding 517
References 518
Part VII: To Market, To Market – 2006 522
Chapter 32. To Market, To Market – 2006 524
References 569
Compound Name, Code Number and Subject Index. Vol. 42 574
Cumulative Chapter Titles Keyword Index, Vol. 1–42 584
Cumulative NCE Introduction Index, 1983–2006 602
Cumulative NCE Introduction Index, 1983–2006 (By Indication) 622
Color Plate Section 644